title: Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States.
abstract: Parkinson's disease is the second most common neurodegenerative disorder, in which both alpha-synuclein (α-syn) and dopamine (DA) have a critical role. α-Syn is known to be natively unstructured in equilibrium with subpopulations of more compact structures. It is these compact structures that are thought to be linked to amyloid formation. In the presence of DA, α-syn yields a diverse range of SDS-resistant, non-amyloid oligomers, however the precursor state conformation has not been established. Here, three DA molecules have been observed to bind per α-syn monomer by electrospray-ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS). Each of these DA molecules binds exclusively to the extended conformation of α-syn, and binding is not observed in the compact state of the protein. Measurements of collisional cross sectional areas show that the incremental uptake of DA pushes the protein towards a highly extended population, becoming fully populated upon the binding of three DA ligands. Tyrosine (Tyr) as a closely related structural analog, exhibited limited binding to the protein as compared with DA, with a maximum of two ligands being observed. Those Tyr ligands that do bind were observed as adducts to the extended conformation akin to DA. These findings suggest DA is able to modulate α-syn self-assembly by inducing the population of a highly extended state.
authors.affiliation: Biomedical Research Centre, Sheffield Hallam University, Sheffield, United Kingdom.
authors.forename: Eva
authors.initials: E
authors.lastname: Illes-Toth
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Dalton
authors.forename: David P
authors.initials: DP
authors.lastname: Smith
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D021241:Spectrometry, Mass, Electrospray Ionization; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D004298:Dopamine